Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization

Nature Cell Biology volume 5, pages 46–52 (2003)Cite this article

Abstract

Several protein complexes that are involved in epithelial apicobasal polarity have been identified1. However, the mechanism by which these complexes interact to form an integrated polarized cell morphology remains unclear. Crumbs (Crb) and Lethal giant larvae (Lgl) are components of distinct complexes that regulate epithelial polarization in Drosophila melanogaster, but may not interact directly as they localize to the apical and basolateral membrane, respectively2,3,4,5,6,7,8,9. Nevertheless, a genetic screen identifies marked functional interactions between crb and lgl. These interactions extend to other genes within the crb (stardust, sdt) and lgl (discs large, dlg; scribble, scrib) pathways. Our findings suggest that the crb and lgl pathways function competitively to define apical and basolateral surfaces. They also suggest that in the absence of lgl pathway activity, the crb pathway is not required to maintain epithelial polarity. Moreover, we show that crb and lgl cooperate in zonula adherens formation early in development. At later stages, epithelial cells in these mutants acquire normal polarity, indicating the presence of compensatory mechanisms. We find that bazooka (baz) functions redundantly with crb/sdt to support apical polarity at mid- to late-embryogenesis. Despite regaining cell polarity, however, epithelial cells in crb and lgl pathway mutants fail to re-establish normal overall tissue architecture, indicating that the timely acquisition of polarized cell structure is essential for normal tissue organization.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genetic interactions between th e crb and lgl pathways.
Figure 2: Junctional differentiation and distribution of polarity markers in lgl mutant embryos.
Figure 3: Distribution of polarity markers and junctional differentiation in late crblof embryos.
Figure 4: Redundant activity of Baz and Sdt in epithelial polarization of post-gastrula embryos.
Figure 5: The role of Crb, Baz and Lgl complexes in epithelial polarity.

Similar content being viewed by others

References

  1. Tepass, U., Tanentzapf, G., Ward, R. & Fehon, R. Epithelial cell polarity and cell junctions in Drosophila. Annu. Rev. Genet. 35, 747–784 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Tepass, U., Theres, C. & Knust, E. crumbs encodes an EGF-like protein expressed on apical membranes of Drosophila epithelial cells and required for organization of epithelia. Cell 6, 787–799 (1990).

    Article  Google Scholar 

  3. Tepass, U. & Knust, E. Phenotypic and developmental analysis of mutations at the crumbs locus, a gene required for the development of epithelia in Drosophila melanogaster. Roux Arch. Dev. Biol. 199, 189–206 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Wodarz, A., Grawe, F. & Knust, E. Crumbs is involved in the control of apical protein targeting during Drosophila epithelial development. Mech. Dev. 44, 175–187 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Wodarz, A., Hinz, U., Engelbert, M. & Knust, E. Expression of Crumbs confers apical character on plasma membrane domains of ectodermal epithelia of Drosophila. Cell 82, 67–76 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Manfruelli, P., Arquier, N., Hanratty, W. P. & Semeriva M. The tumor suppressor gene, lethal(2)giant larvae (1(2)g1), is required for cell shape change of epithelial cells during Drosophila development. Development 122, 2283–2294 (1996).

    CAS  PubMed  Google Scholar 

  7. Bilder, D., Li, M. & Perrimon, N. Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289, 113–116 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Strand, D., Raska, I. & Mechler, B. M. The Drosophila lethal(2)giant larvae tumor suppressor protein is a component of the cytoskeleton. J. Cell Biol. 127, 1345–1360 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Tepass, U. Crumbs, a component of the apical membrane, is required for zonula adherens formation in primary epithelia of Drosophila. Dev. Biol. 177, 217–225 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Grawe, F., Wodarz, A., Lee., B., Knust, E. & Skaer, H. The Drosophila genes crumbs and stardust are involved in the biogenesis of adherens junctions. Development 122, 951–959 (1996).

    CAS  PubMed  Google Scholar 

  11. Strand, D. et al. The Drosophila lethal(2)giant larvae tumor suppressor protein forms homo-oligomers and is associated with nonmuscle myosin II heavy chain. J. Cell Biol. 127, 1361–1373 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Gateff, E. Malignant neoplasms of genetic origin in Drosophila melanogaster. Science 200, 1448–1459 (1978).

    Article  CAS  PubMed  Google Scholar 

  13. Mechler, B. M., McGinnis, W. & Gehring W. J. Molecular cloning of lethal(2)giant larvae, a recessive oncogene of Drosophila melanogaster. EMBO J. 4, 1551–1557 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ohshiro, T., Yagami, T., Zhang, C. & Matsuzaki, F. Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature 408, 593–596 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Peng, C. Y., Manning, L., Albertson, R. & Doe C. Q. The tumour-suppressor genes lgl and dlg regulate basal protein targeting in Drosophila neuroblasts. Nature 408, 596–600 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Tepass, U. & Knust, E. crumbs and stardust function in a genetic pathway that controls the organization of epithelia in Drosophila melanogaster. Dev. Biol. 158, 311–326 (1993).

    Article  Google Scholar 

  17. Bachmann, A., Schneider, M., Theilenberg, E., Grawe, F. & Knust, E. Stardust, a novel Drosophila MAGUK, acts as a partner of Crumbs in the control of epithelial polarity. Nature 414, 638–643 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Hong, Y., Stronach, B., Perrimon, N., Jan, L. Y. & Jan, Y. N. stardust encodes a MAGUK protein that interacts with Crumbs to control polarity of epithelia but not neuroblasts in Drosophila. Nature 414, 634–638 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Roh, M. H. et al. The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost. J. Cell Biol. 157, 161–72 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Woods, D. F. & Bryant, P. J. The discs-large tumor suppressor gene of Drosophila encodes a guanylate kinase homolog localized at septate junctions. Cell 66, 451–464 (1991).

    Article  CAS  PubMed  Google Scholar 

  21. Bilder, D. & Perrimon, N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 403, 676–680 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Perrimon, N. The maternal effect of lethal(1)discs-large-1: a recessive oncogene of Drosophila melanogaster. Dev. Biol. 127, 392–407 (1988).

    Article  CAS  PubMed  Google Scholar 

  23. Müller, H. A. & Wieschaus, E. armadillo, bazooka, and stardust are critical for early stages in formation of the zonula adherens and maintenance of the polarized blastoderm epithelium in Drosophila. J. Cell Biol. 134, 149–163 (1996).

    Article  PubMed  Google Scholar 

  24. Thomas, G. H. & Kiehart, D. P. βHeavy-spectrin has a restricted tissue and subcellular distribution during Drosophila embryogenesis. Development 120, 2039–2050 (1994).

    CAS  PubMed  Google Scholar 

  25. Baumgartner, S. et al. A Drosophila neurexin is required for septate junction and blood-nerve barrier formation and function. Cell 87, 1059–1068 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. White, K. et al. Genetic control of programmed cell death in Drosophila. Science 264, 677–683 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Kuchinke, U., Grawe, F. & Knust E. Control of spindle orientation in Drosophila by the Par-3-related PDZ-domain protein Bazooka. Curr. Biol. 8, 1357–1365 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Wodarz, A., Ramrath, A., Grimm, A. & Knust, E. Drosophila atypical protein kinase C associates with Bazooka and controls polarity of epithelia and neuroblasts. J. Cell Biol. 150, 1361–1374 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Petronczki, M. & Knoblich, J. A. DmPAR-6 directs epithelial polarity and asymmetric cell division of neuroblasts in Drosophila. Nature Cell Biol. 3, 43–49 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Fehon, R. G., Dawson, I. A. & Artavanis-Tsakonas, S. A Drosophila homologue of membrane-skeleton protein 4.1 is associated with septate junctions and is encoded by the coracle gene. Development 120, 545–557 (1994).

    CAS  PubMed  Google Scholar 

  31. Cox, R. T., Kirkpatrick, C. & Peifer, M. Armadillo is required for adherens junction assembly, cell polarity, and morphogenesis during Drosophila embryogenesis. J. Cell Biol. 134, 133–148 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Tanentzapf, G., Smith, C., McGlade, J. & Tepass, U. Apical, lateral, and basal polarization cues contribute to the development of the follicular epithelium during Drosophila oogenesis. J. Cell Biol. 151, 891–904 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tepass, U. Epithelial differentiation in Drosophila. Bioessays 19, 673–682 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Bhat, M. A. et al. Discs Lost, a novel multi-PDZ domain protein, establishes and maintains epithelial polarity. Cell 96, 633–645 (1999).

    Article  Google Scholar 

  35. Pellikka, M. et al. Crumbs, the Drosophila homologue of human CRB1/RP12, is essential for photoreceptor morphogenesis. Nature 416, 143–149 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Medina, E. et al. Crumbs interacts with moesin and βHeavy-spectrin in the apical membrane skeleton of Drosophila. J. Cell Biol. 158, 941–951 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chou, T. B. & Perrimon, N. The autosomal FLP-DFS technique for generating germline mosaics in Drosophila melanogaster. Genetics 144, 1673–1679 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Freeman, M. Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87, 651–660 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  Google Scholar 

  40. Tepass, U. & Hartenstein, V. The development of cellular junctions in the Drosophila embryo. Dev. Biol. 161, 563–596 (1994).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Pellikka for expert assistance. We are grateful to H. Bellen, D. Bilder, D. Branton, P. Bryant, V. Budnik, R. Fehon, F. Matsuzaki, B. Mechler, A. Müller, G. Thomas, U. Thomas, A. Wodarz, the Bloomington Drosophila Stock Center and the Developmental Studies Hybridoma Bank for reagents. We thank D. Bilder for discussion of unpublished data and D. Godt for critical comments on the manuscript. This work was supported by a grant from the Canadian Institute of Health Research (to U.T.).

Author information

Author notes

  1. Guy Tanentzapf

    Present address: Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge, CB2 1QR, UK

Authors and Affiliations

  1. Department of Zoology, University of Toronto, Toronto, M5S 3G5, Ontario, Canada

    Guy Tanentzapf & Ulrich Tepass

Authors
  1. Guy Tanentzapf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulrich Tepass
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich Tepass.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanentzapf, G., Tepass, U. Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization. Nat Cell Biol 5, 46–52 (2003). https://doi.org/10.1038/ncb896

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb896

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing